(R)-methyl 5-(3-(2-formyl-5-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate | 431989-54-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩类
• 英文名称: (R)-methyl 5-(3-(2-formyl-5-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate
• 英文别名: (R)-Methyl 5-(3-(2-formyl-5-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate；methyl 5-[3-[(2R)-2-formyl-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylate
• CAS: 431989-54-7
• 化学式: C₁₄H₁₇NO₄S
• 分子量: 295.359
• InChiKey: TYGXITCKYVKKFC-SNVBAGLBSA-N

物化性质

• 沸点：
  498.5±45.0 °C(Predicted)
• 密度：
  1.312±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  20
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  91.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (R)-methyl 5-(3-(2-formyl-5-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate 在 sodium hydride 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 mineral oil 为溶剂， 反应 4.5h， 生成 5-(3-{(2R)-2-[(1E,3S)-3-hydroxy-4-(3-methylphenyl)but-1-enyl]-5-oxopyrrolidin-1-yl}propyl)thiophene-2-carboxylic acid
  参考文献：
  名称：

  Discovery of novel prostaglandin analogs as potent and selective EP2/EP4 dual agonists

  摘要：

  To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of c-lactam prostaglandin E analogs bearing a 16-phenyl x-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.02.018
• 作为产物：
  描述：

  (R)-methyl 5-(3-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate 生成 (R)-methyl 5-(3-(2-formyl-5-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate
  参考文献：
  名称：

  Discovery of a novel EP2/EP4 dual agonist with high subtype-selectivity

  摘要：

  A series of gamma-lactam prostaglandin E(1) analogs bearing a 16-phenyl moiety in the omega-chain and aryl moiety in the alpha-chain were synthesized and biologically evaluated. Among the tested compounds, gamma-lactam PGE analog 3 designed as a structural hybrid of 1 and 2 was discovered as the most optimized EP2/EP4 dual agonist with excellent subtype-selectivity (K(i) values: mEP2 = 9.3 nM, mEP4 = 0.41 nM). A structure-activity relationship study is presented. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.10.109

文献信息

• [EN] LACTAM COMPOUNDS AS EP4 RECEPTOR-SELECTIVE AGONISTS FOR USE IN THE TREATMENT OF EP4-MEDIATED DISEASES AND CONDITIONS<br/>[FR] COMPOSÉS LACTAMES EN TANT QU'AGONISTES SÉLECTIFS DU RÉCEPTEUR EP4 POUR L'UTILISATION DANS LE TRAITEMENT DE MALADIES ET D'ÉTATS À MÉDIATION PAR EP4
  申请人：CAYMAN CHEMICAL CO INC

  公开号：WO2014144610A1

  公开（公告）日：2014-09-18

  Disclosed herein are compounds of formula (I) wherein L1, L2, L3, R1, R4, R5, and R6 are as defined in the specification. Compounds of formula (I) are EP4 agonists useful in the treatment of glaucoma, osteoporosis, bone fracture, periodontal bone loss, orthopedic implant, alopecia, neuropathic pain, and related disorders. Pharmaceutical compositions and methods of treating conditions or disorders are also described.

  披露了公式(I)的化合物，其中L1、L2、L3、R1、R4、R5和R6如说明书定义。公式(I)的化合物是EP4激动剂，可用于治疗青光眼、骨质疏松症、骨折、牙周骨丢失、骨科植入物、脱发、神经性疼痛及相关疾病。还描述了药物组合物和治疗条件或疾病的方法。
• LACTAM COMPOUNDS AS EP4 RECEPTOR-SELECTIVE AGONISTS FOR USE IN THE TREATMENT OF EP4-MEDIATED DISEASES AND CONDITIONS
  申请人：CAYMAN CHEMICAL COMPANY, INC.

  公开号：US20160060216A1

  公开（公告）日：2016-03-03

  Disclosed herein are compounds of formula (I) wherein L 1 , L 2 , L 3 , L 4 , R 1 , R 4 , R 5 , R 6 , and s are as defined in the specification. Compounds of formula (I) are EP 4 agonists useful in the treatment of glaucoma, osteoporosis, bone fracture, periodontal bone loss, orthopedic implant, alopecia, neuropathic pain, and related disorders. Pharmaceutical compositions and methods of treating conditions or disorders are also described.

  披露了公式(I)的化合物 其中L 1 , L 2 , L 3 , L 4 , R 1 , R 4 , R 5 , R 6 ，和s如说明书所定义。 公式(I)的化合物是EP 4 激动剂，用于治疗青光眼、骨质疏松症、骨折、牙周骨丢失、矫形植入物、脱发、神经性疼痛和相关的疾病。 还描述了药物组合物和治疗条件或疾病的方法。
• Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and an EP2 or EP4 selective agonist
  申请人：Lee G. Andrew

  公开号：US20050065133A1

  公开（公告）日：2005-03-24

  The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a 2-alkylidene-19-nor-vitamin D derivative and an EP 2 or EP 4 selective agonist or a pharmaceutically acceptable salt or prodrug thereof. Particularly, the present invention relates to pharmaceutical compositions and methods comprising administering to a patient in need thereof 2-methylene-19-nor-20(S)-1α,25-dihydroxyvitamin D 3 and an EP 2 or EP 4 selective agonist or a pharmaceutically acceptable salt or prodrug thereof.

  本发明涉及制药组合物和治疗方法，包括向需要的患者施用2-烷基亚甲基-19-去氢维生素D衍生物和EP2或EP4选择性激动剂或其药用可接受的盐或前药的组合物。特别地，本发明涉及制药组合物和方法，包括向需要的患者施用2-亚甲基-19-去氢-20(S)-1α,25-二羟基维生素D3和EP2或EP4选择性激动剂或其药用可接受的盐或前药。
• EP4 receptor selective agonists in the treatment of osteoporosis
  申请人：——

  公开号：US20020065308A1

  公开（公告）日：2002-05-30

  This invention is directed to EP4 receptor selective prostaglandin agonists of the Formula I, 1 wherein R 2 , X, Z and Q are as defined in the specification. This invention is also directed to pharmaceutical compositions containing those compounds. This invention is also directed to methods of treating conditions which present with low bone mass, particularly osteoporosis, frailty, an osteoporotic fracture, a bone defect, childhood idiopathic bone loss, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth in a mammal comprising administering those compounds.

  这项发明针对公式I中的EP4受体选择性前列腺素激动剂，其中R2、X、Z和Q的定义如规范中所述。该发明还涉及含有这些化合物的药物组合物。该发明还涉及治疗低骨密度症状的方法，特别是骨质疏松症、虚弱、骨折、骨缺损、儿童特发性骨量减少、牙槽骨丧失、下颌骨丧失、骨折、骨切开术、与牙周炎相关的骨丧失或哺乳动物体内假体生长中的骨丧失，包括给予这些化合物。
• [EN] CONTINUOUS COMBINATION THERAPY WITH SELECTIVE PROSTAGLANDIN EP4, RECEPTOR AGONISTS AND AN ESTROGEN FOR THE TREATMENT OF CONDITIONS THAT PRESENT WITH LOW BONE MASS<br/>[FR] POLYTHERAPIE CONTINUE AVEC DES AGONISTES SELECTIFS DES RECEPTEURS EP4 DE LA PROSTAGLANDINE ET UN OESTROGENE POUR LE TRAITEMENT DE PATHOLOGIES SE MANIFESTANT PAR UNE FAIBLE MASSE OSSEUSE
  申请人：PFIZER PROD INC

  公开号：WO2005060946A1

  公开（公告）日：2005-07-07

  This invention is directed to methods for treating conditions which present with low bone mass in a patient in need thereof using continuous combination therapy with a synergistically effective combination of an EP4 receptor selective agonist or a pharmaceutically acceptable salt thereof, such as 5-(3-2S-[3R-hydroxy­4-(3-trifluoromethyl-phenyl)-butyl]-5-oxo-pyrrolid in-1-yl}-propyl)-thiophene-2­carboxylic acid or a pharmaceutically acceptable salt thereof; and an estrogen or a pharmaceutically effective salt thereof. The present methods are useful for treating conditions that present with low bone mass including osteoporosis, osteotomy, osteoporotic fracture, childhood idiopathic bone loss, periodontitis and low bone mass and for enhancing bone healing following facial reconstruction, maxillary reconstruction or mandibular reconstruction, inducing vertebral synostosis, enhancing long bone extension, enhancing the healing rate of a bone graft or a long bone fracture or enhancing prosthetic ingrowth in a patient in need thereof.

  本发明涉及使用具有协同作用的EP4受体选择性激动剂或其药学上可接受的盐（例如5-（3-2S-[3R-羟基-4-（3-三氟甲基苯基）-丁基]-5-氧代吡咯烷-1-基}-丙基）-噻吩-2-羧酸或其药学上可接受的盐）和雌激素或其药学上有效的盐的连续联合疗法，用于治疗患有低骨密度的患者的疾病。本方法适用于治疗低骨密度症状，包括骨质疏松症、骨切开术、骨质疏松性骨折、儿童特发性骨质流失、牙周炎和低骨质量，以及增强面部重建、上颌重建或下颌重建后的骨愈合，诱导椎体融合，增强长骨延长，增强骨移植或长骨骨折的愈合速度或增强患者的假体生长。